Ultra low dose oral contraceptives with less menstrual bleeding and sustained efficacy

ABSTRACT

A method of female contraception involves administering a combination of estrogen and progestin for 60-110 consecutive days in which the daily amounts of estrogen and progestin are equivalent to about 5-35 mcg of ethinyl estradiol and about 0.025 to 10 mg of norethindrone acetate, respectively. The advantages include less menstrual bleeding, less patient anemia, less total exposure to medication, higher compliance rates and more lifestyle convenience for patients.

BACKGROUND OF THE INVENTION

The ovarian/menstrual cycle is a complex event characterized by anestrogen rich follicular phase and, after ovulation, a progesterone richluteal phase. Each has a duration of approximately 14 days resulting inan intermenstrual interval of about 28 days. The endometrial tissueresponds to the changes in hormonal milieu.

The onset of menstruation is the beginning of a new menstrual cycle andis counted as day 1. During a span of about 5 to 7 days, the superficiallayers of the endometrium, which grew and developed during theantecedent ovarian/menstrual cycle, are sloughed because demise of thecorpus luteum in the non-fertile menstrual cycle is associated with aloss of progesterone secretion. Ovarian follicular maturation occursprogressively resulting in a rise in the circulating levels of estrogen,which in turn leads to new endometrial proliferation.

The dominant ovarian follicle undergoes ovulation at mid-cycle,generally between menstrual cycle days 12 to 16 and is converted from apredominantly estrogen source to a predominantly progesterone source(the corpus luteum). The increasing level of progesterone in the bloodconverts the proliferative endometrium to a secretory phase in which thetissue proliferation has promptly abated, leading to the formation ofendometrial glands or organs. When the ovulated oocyte is viablyfertilized and continues its progressive embryonic cleavage, thesecretory endometrium and the conceptus can interact to bring aboutimplantation (nidation), beginning about 6 to 8 days afterfertilization.

If an ongoing pregnancy is to be established via implantation, theembryo will attach and burrow into the secretory endometrium and beginto produce human chorionic gonadotropin (HCG). The HCG in turnstimulates extended corpus luteum function, i.e. the progesteroneproduction remains elevated, and menses does not occur in the fertilemenstrual cycle. Pregnancy is then established.

In the non-fertile menstrual cycle, the waning level of progesterone inthe blood causes the endometrial tissue to be sloughed. This starts asubsequent menstrual cycle.

Because endometrial proliferation serves to prepare the uterus for animpending pregnancy, manipulation of hormones and of the uterineenvironment can provide contraception. For example, estrogens are knownto decrease follicle stimulating hormone secretion by feedbackinhibition. Under certain circumstances, estrogens can also inhibitluteinizing hormone secretion, once again by negative feedback. Undernormal circumstances, the spike of circulating estrogen found just priorto ovulation induces the surge of gonadotropic hormones that occurs justprior to and resulting in ovulation. High doses of estrogen immediatelypost-coitally also can prevent conception probably due to interferencewith implantation.

Progestins can also provide contraception. Endogenous progesterone afterestrogen is responsible for the progestational changes of theendometrium and the cyclic changes of cells and tissue in the cervix andthe vagina. Administration of progestin makes the cervical mucus thick,tenacious and cellular which is believed to impede spermatozoaltransport. Administration of progestin also inhibits luteinizing hormonesecretion and blocks ovulation in humans.

The most prevalent form of oral contraception is a pill that combinesboth an estrogen and a progestin, a so-called combined oralcontraceptive preparation.

Alternatively, there are contraceptive preparations that compriseprogestin only. However, the progestin-only preparations have a morevaried spectrum of side effects than do the combined preparations,especially more breakthrough bleeding. As a result, the combinedpreparations are the preferred oral contraceptives in use today (Shethet al., Contraception 25:243, 1982).

Whereas the conventional 21 day pill packs with a 7 day "pill free" orplacebo interval worked well when oral contraceptives were of higherdosage, as the doses have come down, for both the estrogen and progestincomponents, bleeding problems have increased in frequency, especially inthe early months of oral contraceptive use, but even persistently so insome patients.

Since the advent of combined estrogen-progestin medications as oralcontraceptives, there has been a steady downward adjustment of the dailyestrogen dosage. Concurrently, where exposure to the progestin componenthas also been lowered, reduced androgenicity has remained an ongoingpriority. Together these adaptions in formulation have been presented ina variety of regimens, both monophasic and multiphasic. Each have theirown advantages and disadvantages. All-in-all, today's oralcontraceptives are much safer with regard to the incidence and severityof estrogen-linked clotting disorders as well as the suggestedcumulative impact of more "lipid friendly" progestins that maintain thepotentially advantageous high density lipoprotein cholesterol levels incirculation.

U.S. Pat. No. 4,390,531 teaches a triphasic regimen in which each phaseuses about 20-40 mcg ethinyl estradiol, phases 1 and 3 use 0.3-0.8norethindrone and phase 2 doubles the amount of the norethindrone. Thesethree phases consume 21 days of a 28 day cycle. European publishedapplication 0 226 279 states that this regimen is associated with a highincidence of breakthrough bleeding and substitutes a three phase oralcontraceptive regimen using a relatively low amount of ethinyl estradiol(10-50 μg) and a relatively high amount of norethindrone acetate(0.5-1.5 mg) in each phase provided that the amount of estrogen in anytwo phases is never the same. A "rest" phase of about 7 days is used inthis regimen.

U.S. Pat. No. 5,098,714 teaches an osmotic, oral dosage form. One "pill"is administered per day but the administration is, in effect,polyphasic. The dosage form is constructed such that it provides aninitial pulse delivery of estrogen and progestin followed by prolongeddelivery of estrogen.

European published patent application 0 253 607 describes a monophasiccontraceptive preparation containing units having 0.008-0.03 mg ofethinyl estradiol and 0.025-0.1 mg of desogestrel (or equivalent) and aregimen where the preparation is administered over a 23-25 day period,preferably 24 days, followed by a 2-5 day pill-free period. The objectof this regimen is to provide hormonal replacement therapy andcontraceptive protection for the pre-menopausal woman in need thereof bysupplying a low dose of an estrogen combined with a "very low dose of aprogestogen."

In 1989, the accumulating data from the evolution of oral contraceptivepill formulations containing only 20-35 μg of estrogen per day spurredthe Food and Drug Administration's Fertility and Maternal Health DrugsAdvisory Committee to recommend indication of low dose oralcontraceptives for healthy, non-smoking women even during theperimenopausal years, such as, for instance, ages 35-50. In Japan, oralcontraceptives are being evaluated for safety and efficacy, as well associal acceptability, for the first time.

U.S. Pat. No. 5,552,394 describes a method of female contraception whichis characterized by a reduced incidence of breakthrough bleeding afterthe first cycle involves monophasicly administering a combination ofestrogen and progestin for 23-25 consecutive days of a 28 day cycle inwhich the daily amounts of estrogen and progestin are equivalent toabout 5-35 mcg of ethinyl estradiol and about 0.025 to 10 mg ofnorethindrone acetate, respectively and in which the weight ratio ofestrogen to progestin is at least 1:45 calculated as ethinyl estradiolto norethindrone acetate.

In establishing a estrogen-progestin regimen for oral contraceptives,two principal issues must be confronted. First, efficacy must bemaintained and second, there must be avoidance of further erosion in thecontrol of endometrial bleeding. In general, even the lowest dose oralcontraceptive products commercially available have demonstrated efficacybut the overall instances of bleeding control problems has increased asthe doses were reduced, as manifest both in breakthrough bleeding(untimely flow or spotting) or withdrawal amenorrhea during the "pillfree" week (expected menses).

It is the object of the present invention to provide a newestrogen-progestin combination and/or regimen for oral contraceptive usewhich maintains the efficacy and provides enhanced control ofendometrial bleeding. The regimen enhances compliance by involving fewerstop/start transitions per year and also results in less blood loss inpatients with anemia. Having fewer menstrual intervals can enhancelifestyles and convenience. This and other objects of the invention willbecome apparent to those skilled in the art from the following detaileddescription.

SUMMARY OF THE INVENTION

This invention relates to a method of female contraception which ischaracterized by a reduced number of withdrawal menses per year. Moreparticularly, it relates to a method of female contraception whichinvolves administering, preferably monophasicly, a combination ofestrogen and progestin for 60-110 consecutive days followed by 3-10 daysof no administration, in which the daily amounts of the estrogen andprogestin are equivalent to about 5-35 mcg of ethinyl estradiol andabout 0.025-10 mg of norethindrone acetate, respectively.

DESCRIPTION OF INVENTION

In accordance with the present invention, a women in need ofcontraception is administered a combined dosage form of estrogen andprogestin, preferably monophasicly, for 60 to 110 consecutive days,preferably about 80-90 days, followed by an administration free intervalof 3 to 10 days, preferably about 5-8 days, in which the daily amountsof estrogen and progestin are equivalent to about 5-35 mcg of ethinylestradiol and about 0.025 to 10 mg of norethindrone acetate,respectively. On a schedule of 84 days administration followed by 7 pillfree days, there are only four treatment and menstrual cycles per year.

The preferred estrogen and progestins are ethinyl estradiol andnorethindrone acetate although other estrogens and progestins can beemployed. The weight ratio of these two active ingredients is at least1:45 and preferably at least 1:50. The preferable amount of ethinylestradiol is about 10-20 mcg and the preferable amount of thenorethindrone acetate is about 0.25-1.5 mg. Other estrogens vary inpotency from ethinyl estradiol. For example, 30 mcg of ethinyl estradiolis roughly equivalent to 60 mcg of mestranol or 2,000 mg of 17β-estradiol. Likewise, other progestins vary in potency fromnorethindrone acetate. Thus, 3.5 mg of norethindrone acetate is roughlyequivalent to 1 mg of levonorgestrel or desogestrel and3-ketodesogestrel and about 0.7 mg of gestodene. The values given aboveare for the ethinyl estradiol and the norethindrone acetate and if adifferent estrogen or progestin is employed, an adjustment in the amountbased on the relative potency should be made. The correlations inpotency between the various estrogens and progestins are known.

Other useable estrogens include the esters of estradiol, estrone andethinyl estradiol such as the acetate, sulfate, valerate or benzoate,conjugated equine estrogens, agnostic anti-estrogens, and selectiveestrogen receptor modulators. The estrogen is administered in theconventional manner by any route where it is active, for instance orallyor transdermally. Most estrogens are orally active and that route ofadministration is therefore preferred. Accordingly, administration formscan be tablets, dragees, capsules or pills which contain the estrogen(and preferably the progestin) and a suitable pharmaceuticallyacceptable carrier.

Pharmaceutical formulations containing the progestin and a suitablecarrier can be solid dosage forms which includes tablets, capsules,cachets, pellets, pills, powders or granules; topical dosage forms whichincludes solutions, powders, fluid emulsions, fluid suspensions,semi-solids, ointments, pastes, creams, gels or jellies, foams andcontrolled release depot entities; and parenteral dosage forms whichincludes solutions, suspensions, emulsions or dry powder comprising aneffective amount of progestin as taught in this invention. It is knownin the art that the active ingredient, the progestin, can be containedin such formulations in addition to pharmaceutically acceptablediluents, fillers, disintegrants, binders, lubricants, surfactants,hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers,humectants, moisturizers, solubilizers, preservatives and the like. Themeans and methods for administration are known in the art and an artisancan refer to various pharmacologic references for guidance. For example,"Modern Pharmaceutics", Banker & Rhodes, Marcel Dekker, Inc. 1979;"Goodman & Gilman's The Pharmaceutical Basis of Therapeutics", 6thEdition, MacMillan Publishing Co., New York 1980 can be consulted.

The pharmaceutical formulations may be provided in kit form containingat least about 60, and preferably at least about 84 tablets, and up to110 tablets, intended for ingestion on successive days. Preferablyadministration is daily for at least 60 days using tablets containingthe both the estrogen and the progestin and then for at least 3 dayswith placebo.

In order to further illustrate the present invention, specific examplesare set forth below. It will be appreciated, however, that theseexamples are illustrative only and are not intended to limit the scopeof the invention.

EXAMPLE 1

A study is carried out at a fully accredited animal research facilitywhich complies through its animal care and use committee with the reviewstandards set forth in the National Institute of Health's "Guide forCare and Use of Laboratory Animals", the Public Health Services'"Principles for the Care and Use of Laboratory Animals", and the UnitedStates Department of Agriculture's Implementation Regulations of the1985 Amendments for the Animal Welfare Act.

Ten adult female cynomolgus monkeys (macaca fasicularis) having regularpresumably ovulatory menstrual cycles (28.9±3.1 days for the month priorto study entry) are selected. Their duration of spontaneous menses is3.4±1.4 days. Mean body weight of the monkeys is 4.9±1.1 kg (X ±SEM).They are housed individually in a controlled environment (12 hours oflight and 23° C.). Their diet is a commercial primate food (Purina, St.Louis, Mo.) with water ad libitum.

The monkeys are divided at random into two groups (N=5 each). Thestudies begin with spontaneous menstruation in a pretreatment controlcycle. At the onset of the next spontaneous menses, alternatively, theyare assigned to receive on cycle day one an ultra low dose oralcontraceptive for either 60 consecutive days, followed by 3non-treatment days or 84 consecutive days, followed by a 7 non-treatmentdays. These regimens are continued through three treatment cycles. Thestudy concludes with each group of primates being followed during apost-treatment spontaneous ovarian menstrual cycle.

Femoral blood is collected daily and the serum frozen for subsequent RIAof estradiol, progesterone, FSH and LH in the pretreatment andpost-treatment cycles and every 3rd day during all three treatmentcycles, except daily through the "pill free" interval. Bleeding profilesare kept by daily vaginal swabs, indicating spontaneous menstruation,withdrawal bleeding, breakthrough bleeding, or withdrawal amenorrhea.Breakthrough bleeding is defined as detectable blood in the vaginaoutside of the first 8 days after the last dose of oral contraceptive orthe onset of spontaneous menses in non-treatment cycles.

Since the objective is to test an ultra low dose oral contraceptive, themedication is adjusted to fit the smaller (than human) body weight ofthese laboratory primates. The dose of ethinyl estradiol is 1.2 μg/day,while the dose of norethindrone acetate is 0.06 mg/day. This "in-house"reformulation is achieved by grinding to powder a commercially availablemonophasic pill (Loestrin 1/20, Parke Davis, Morris Plains, N.J.), whichoriginally contained 1 mg of norethindrone acetate and 20 μg of ethinylestradiol per tablet, contained in a conventional 21 day pack along with7 iron-containing placebos.

In terms of comparison to human dose equivalents, the daily dosereceived by the monkeys (with a monkey's body weight about 5 kg and awoman's at 50 kg) is about 12 μg of ethinyl estradiol and 0.6 mg ofnorethindrone acetate. Thus, this ultra low dose oral contraceptiveformulation presented a 40% reduction in daily estrogen-progestinexposure as compared to one of the lowest estrogen dose combination oralcontraceptives commercially available today in America or Europe. Takinginto account that when a continuous 84 day ultra low dose regimen plus a7 dy pill free interval was used, versus the traditional 21+7 dayprotocol, that there would be 63 more doses on an annualized basis,still the exposure to medication was reduced by more than 26% yearly,compared to the commercial product Loestrin 1/20.

EXAMPLES 2-5

The example 1 procedure is repeated using the following combinations ofestrogen and progestin:

    ______________________________________                                    Treatment    Example  Estrogen     Progestin Days    ______________________________________    2        mestranol    levo-     84                          norgestrel    3        17-beta-     3-keto-   110             estradiol    desogestrel    4        ethinyl      desogestrel                                    80             estradiol    5        mestranol    gestodone 60    ______________________________________

Application of the compounds, compositions and methods of the presentinvention for the medical or pharmaceutical uses described can beaccomplished by any clinical, medical, and pharmaceutical methods andtechniques as are presently or prospectively known to those skilled inthe art. It will therefore be appreciated that the various embodimentswhich have been described above are intended to illustrate the inventionand various changes and modifications can be made in the inventivemethod without departing from the spirit and scope thereof.

What is claimed is:
 1. A method of female contraception which comprisesmonophasicly administering to a pre-menopausal female a combination ofestrogen and progestin for 60-110 consecutive days in which the dailyamounts of estrogen and progestin are equivalent to about 5-35 mcg ofethinyl estradiol and about 0.025 to 10 mg of norethindrone acetate,respectively, following by non-administration for a period of 3-10 days.2. The method of claim 1 in which the daily amount of estrogen isequivalent to about 10 to 20 mcg of ethinyl estradiol.
 3. The method ofclaim 2 in which the daily amount of progestin is equivalent to 0.25-1.5mg of norethindrone acetate.
 4. The method of claim 3 in which thecombination is administered for at least 80 consecutive days.
 5. Themethod of claim 4 in which the estrogen is ethinyl estradiol.
 6. Themethod of claim 5 in which the progestin is norethindrone acetate. 7.The method of claim 1 in which the daily amount of progestin isequivalent to 0.25-1.5 mg of norethindrone acetate.
 8. The method ofclaim 1 in which the combination is administered for at least 80consecutive days.
 9. The method of claim 1 in which the estrogen isethinyl estradiol.
 10. The method of claim 1 in which the progestin isnorethindrone acetate.
 11. The method of claim 1 in which the dailyamount of estrogen is up to 30 mcg of ethinyl estadiol.